ABSTRACT Developmental neuropsychiatric disorders are increasingly viewed as `developmental dysconnectivity' disorders characterized by pathological patterns of neural connectivity. However, to date investigational approaches to unravel the elusive pathophysiological basis of these phenomena are limited. Modeling specific copy number variants (CNVs) that are strongly associated with distinct neurodevelopmental outcomes offers an extraordinary opportunity to investigate the same genetic defect across species. The 22q11.2 microdeletion (22q11DS) is a well-established potent risk factor for psychosis, conferring at least 25 times the general population base rate. This CNV offers a particularly valuable investigational model, given that large patient cohorts have been identified and extensively characterized at both behavioral and neuroanatomic levels. Importantly, the close homology between human Chromosome 22 and portions of mouse chromosome 16 allows for precise modeling of the causal CNV. Mouse models allow direct assessment of brain mechanisms associated with CNVs while reducing variability due to genetic and environmental factors. The identification of analogous functional connectivity hubs in preclinical species like the mouse may provide critical insight into the elusive biological underpinnings of these connectional alterations. Yet, to date, truly translational studies in which the same genetic defect is modeled in animals and human patients are almost non-existent. Here, we propose to elucidate the cellular underpinnings of structural and functional large-scale connectivity alterations, in the context of this specific well-characterized genetic etiology, using novel methodologies in parallel mouse and human studies. In particular, we aim to: 1) Map macroscale networks, and their developmental trajectories, in human 22q11.2 deletion carriers and the 22q11DS mouse model, in comparison to typically developing controls and wild-type mice, order to investigate the cellular correlates of disrupted long-range connectivity; 2) Investigate developmental rescue of macroscale connectivity defects, at both the neural and behavioral levels; and 3) Investigate social behavioral correlates of connectivity alterations, using parallel tasks of social preference and social reward across species. Collectively, this work will provide a key proof of principle for future translational studies of neurodevelopmental genes and their contribution to large-scale connectivity alterations, and will inform whether neural connectivity may be a viable biomarker (complementary to behavior) for evaluation of novel treatments.